Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

Article ID	Journal	Published Year	Pages	File Type
10801710	Biochimica et Biophysica Acta (BBA) - Molecular Cell Research	2016	49 Pages	PDF

Abstract

Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3KÎ´) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Keywords

NF-κB PI3K LPS PD-1 dsDNA BCR MYD88 PD-L1 bFGF SDF-1 ERK FDC NLC PIM ET-1 TLR PKC HMGB1 NAMPT Bcl2 BMSC CCL PDGF RAGE STAT-3 ETAR CXCL BCMA VCAM-1 CLL HLA-G VLA-4 ssDNA NRP1 CD40L SH2 LTβR CXCR TACI natural killer group 2 member D BAFFR BAFF receptor ZAP70 ITAM IGHV Ox-LDL lymphotoxin beta receptor B-cell maturation antigen C-C motif ligand SF3B1 Vascular cell-adhesion molecule-1 Shp1 BAG6 BCR signaling HS1 NKP30 HCDR3 TNF CTLA-4 PLC-γ2 human leukocyte antigen G C-X-C motif ligand PD-1 ligand BIRC3 ataxia telangiectasia mutated Btk Single-stranded DNA double-stranded DNA MAPK Mcl1 APRIL endothelin 1 surface immunoglobulin interleukin BAFF Syk TAM toll like receptor Tumor associated macrophage Bruton's tyrosine kinase SIG ATM very late antigen-4 Bone marrow stromal cell stromal cells follicular dendritic cell spleen tyrosine kinase Stromal cell derived factor 1 B-cell activating factor Vascular endothelial growth factor Vascular Endothelial Growth Factor (VEGF)platelet-derived growth factor basic fibroblast growth factor tumor necrosis factor nuclear factor kappa B phosphoinositide-3-kinase transmembrane activator and calcium modulator and cyclophilin ligand interactor Fibronectin B-cell lymphoma 2 Myeloid cell leukemia 1 Chronic lymphocytic leukemia Oxidized low-density lipoprotein lipopolysaccharide CD40 ligand signal transducer and activator of transcription 3 immunoglobulin heavy chain variable region immunoreceptor tyrosine-based activation motif NAD neuropilin-1 nicotinamide adenine dinucleotide Src Homology 2 cytotoxic T-lymphocyte-associated protein 4 programmed cell death protein 1 Protein kinase C mitogen-activated protein kinase High mobility group box 1 extracellular signal-regulated kinase B cell receptor a proliferation-inducing ligand